U.S. Pat. No. 4,198,415 discloses a group of octahydropyrazolo[3,4-g]quinolines useful as prolactin inhibitors and in the treatment of Parkinsonism. The compounds disclosed therein are said to have D-2 dopamine agonist (dopaminergic) activity, according to Tsuruta et al Nature, 292, 463 (1981). One of the more active drugs disclosed carries an n-propyl group on the quinoline nitrogen.
A key intermediate in the preparation of these octahydropyrazolo[3,4-g]quinolines is a transdl-1-alkyl-6-oxodecahydroquinoline, one of whose stereoisomers (the 4a.alpha., 8a.beta. compound) is disclosed in VII of column 5 of U.S. Pat. No. 4,198,415. The same intermediate is used to prepare a related group of compounds, the 4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinolines of U.S. Pat. No. 4,235,909, --see compound VII, column 3, lines 50-60 (the compound represented by VII is a typographical error since it lacks the keto group at 6. This error has been noted in the file of U.S. Pat. No. 4,235,909, since it is clear from the context that VII should have a ketone group at C-6). The octahydro-2H-pyrrolo[3,4-g]quinolines are similar in activity to the octahydro-1H(and 2H)-pyrazolo[3,4-g]quinolines in that the compounds are inhibitors of prolactin secretion and also show activity in experimental models of Parkinson's disease.
U.S. Pat. No. 4,198,415 also discloses the reduction of a mixture of double bond isomers, dl-1-alkyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinolihe and dl-1-alkyl-6-hydroxy-1,2,3,4,4a,5,6,7-octahydro quinoline with NaBH.sub.3 CN to yield trans-dl-1-alkyl-6-hydroxydecahydroquinoline.
The hydrogenation of a 6-methoxyquinoline is shown in Honel et al, J.C.S. Perkin I, 1980, 1933. Hydrogenation over platinum in neutral or weakly acidic media results in hydrogenation of the pyridine ring, whereas hydrogenation in acidic (12N HCl or CF.sub.3 COOH) results in hydrogenation of the benzene ring. Birch reduction of a 6-methoxy-1-benzyl 1,2,3,4-tetrahydroisoquinoline is shown in Okieman et al, J. Roy. Neth. Chem. Soc., 99 353 (1980). Reduction of 1-methyl-1,2,3,4-tetrahydroquinoline to a mixture of 1-methyloctahydroquinolines is shown in Leonard et al, J. Org. Chem. 27, 4027 (1962). Lithium and isopropylamine was the reducing agent. In this instance, Birch reduction introduced 4 hydrogens into the benzene ring. Birch et al J.C.S., 637 (1971) reduced a series of N,N-dimethylanilines with Li in liquid ammonia to produce conjugated cyclohexadiene amines. In general, m and p-anisidines (m and p-methoxy dimethyl anilines) gave the conjugated cyclohexadiene on Birch reduction but the ortho derivative gave the nonconjugated (page 638, formula 3) diene. Reduction of N-(p-methoxyphenyl)morpholine, according to Birch and Dyke, Aust. J. Chem., 31, 1625 (1978) also gave the unconjugated diene on reduction with Li and liquid NH.sub.3. Both of these reductions involved exocyclic amine functions attached to a benzene ring system containing also a p-methoxy group. Reductions of endocyclic amines, as in an N-alkyl 6-methoxytetrahydroquinoline, are not recorded.
Finally Borch et al, J.A.C.S., 93, 2897 (1971) discuss the reduction of enamines with NaBH.sub.3 CN. No instance of a reduction of an endocyclic double bond of an enamine in which the ring contains a second double bond, has been found.
The method of synthesizing trans-dl-1-alkyl-6-oxodecahydroquinolines, as disclosed in U.S. Pat. Nos. 4,198,415 and 4,235,909 patents, while operative, involves five steps from a commercially available starting material. Furthermore, yields are not as high as desirable for a commercial process.
It is an object of this invention to provide an improved method of preparing trans-dl-1-alkyl-6-oxodecahydroquinolines which is easier to carry out and which gives higher yields than the process previously used.